Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Canada.
Thorax. 2017 Jun;72(6):538-549. doi: 10.1136/thoraxjnl-2016-209501. Epub 2017 Feb 3.
Hypercapnia is common in mechanically ventilated patients. Experimentally, 'therapeutic hypercapnia' can protect, but it can also cause harm, depending on the mechanism of injury. Hypercapnia suppresses multiple signalling pathways. Previous investigations have examined mechanisms that were known a priori, but only a limited number of pathways, each suppressed by CO, have been reported.
Because of the complexity and interdependence of processes in acute lung injury, this study sought to fill in knowledge gaps using an unbiased screen, aiming to identify a specifically upregulated pathway.
Using genome-wide gene expression analysis in a mouse model of ventilator-induced lung injury, we discovered a previously unsuspected mechanism by which CO can protect against injury: induction of the transporter protein for α-tocopherol, α-tocopherol transfer protein (αTTP). Pulmonary αTTP was induced by inspired CO in two in vivo murine models of ventilator-induced lung injury; the level of αTTP expression correlated with degree of lung protection; and, absence of the αTTP gene significantly reduced the protective effects of CO. α-Tocopherol is a potent antioxidant and hypercapnia increased lung α-tocopherol in wild-type mice, but this did not alter superoxide generation or expression of NRF2-dependent antioxidant response genes in wild-type or in αTTP mice. In concordance with a regulatory role for α-tocopherol in lipid mediator synthesis, hypercapnia attenuated 5-lipoxygenase activity and this was dependent on the presence of αTTP.
Inspired CO upregulates αTTP which increases lung α-tocopherol levels and inhibits synthesis of a pathogenic chemoattractant.
高碳酸血症在机械通气患者中很常见。在实验中，“治疗性高碳酸血症”可以起到保护作用，但也可能造成伤害，这取决于损伤的机制。高碳酸血症会抑制多种信号通路。先前的研究已经检查了预先已知的机制，但据报道，只有有限数量的通路（每种通路都被 CO 抑制）被抑制。
由于急性肺损伤过程的复杂性和相互依赖性，本研究试图使用无偏筛选来填补知识空白，旨在确定一个具体上调的通路。
我们使用呼吸机诱导肺损伤的小鼠模型进行全基因组基因表达分析，发现了 CO 可以起到保护作用的一个先前未被怀疑的机制：诱导α-生育酚的转运蛋白，α-生育酚转移蛋白（αTTP）。在两种呼吸机诱导肺损伤的体内小鼠模型中，吸入的 CO 诱导了肺部 αTTP；αTTP 的表达水平与肺保护程度相关；并且，αTTP 基因的缺失显著降低了 CO 的保护作用。α-生育酚是一种有效的抗氧化剂，高碳酸血症增加了野生型小鼠肺部的α-生育酚，但这并没有改变超氧化物的产生或 NRF2 依赖性抗氧化反应基因的表达，无论是在野生型还是αTTP 小鼠中。与α-生育酚在脂质介质合成中的调节作用一致，高碳酸血症减弱了 5-脂氧合酶的活性，而这依赖于 αTTP 的存在。
吸入的 CO 上调了 αTTP，增加了肺部的α-生育酚水平并抑制了致病趋化因子的合成。
